Chemistry Reference
In-Depth Information
used
O
-methyloximes as the masked equivalent of aldehydes in their development
of c-Src inhibitors.
[
40
]
A set of 305 aldehydes was selected and were capped with
O
-methylhydroxylamine to make a library of
O
-methyloximes. The library was screened
against c-Src and hit fragments were identified. The parent aldehydes, corresponding to the
O
-methyloximes found to be active, were then used for the synthesis of a combinatorial
library of linked binding fragments using flexible linking groups. Screening of this library
successfully identified a highly potent inhibitor (IC
50
64 nM). It is noteworthy that the IC
50
s
of the original fragment hits were only in the region of 40 μM.
The unmasked versions of each screening fragment can also be assembled as a separate
complementary set to the fragment library. This fragment pairing concept has been cham-
pioned by the group at Novartis.
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]
A matching pair of synthesis and screening fragments
are selected using a dictionary of reactions suitable for functional group interconversion
(Figure 3.1).
O
O
O
O
Cl
N
H
H
N
N
N
O
Synthesis fragment
Screening fragment
Figure 3.1
Examples for pairs of screening and synthesis fragments.
The masked functionality does not necessarily have to have an unmasked counterpart.
It can also be a simple synthetic handle which is inert under screening conditions but can
be activated in a controlled manner, for example, by catalysis. Examples of such catalytic
reactions include Suzuki coupling, which is a palladium-catalysed cross-coupling reaction
between an organoborane and an aryl halide and is used widely as an extremely powerful
tool for C-C bond formation. The team at SGX Pharmaceuticals designed their fragment
library for X-ray crystallographic screening so that approximately half of the compounds
in the fragment library contain one or more bromine atoms (aryl bromides) which can be
used as synthetic handles. Further, the presence of bromine not only facilitates synthetic
elaboration of the screening hits, but also permits unambiguous bromine atom identification
in experimental electron density maps. The X-ray wavelength can be adjusted during the
diffraction data collection to allow detection of anomalous dispersion signals unique to
bromine.
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26
]
Another example of such a catalytic reaction that satisfies the requirements
